Project Summary: The process of tumorigenesis generally results from multiple, sequential genetic and epigenetic changes that affect a number of cellular processes including growth, survival, invasiveness, and metastatic capabilities of the tumor. Pancreatic ductal adenocarcinoma, the primary cancer of the pancreas, is associated with activating mutations in the Kras gene, loss of multiple tumor suppressor genes, and increased expression of epidermal growth factor receptor (EGFR) signaling components. Understanding how each of these events affects tumorigenesis is essential to developing treatment that will target the most critical components of tumor growth, survival, and metastasis. Furthermore, understanding which genetic or epigenetic events occur early in tumorigenesis may lead to biomarkers for earlier detection of pancreatic cancer. Mouse models have recently delineated Kras mutation as a potent initiator of pancreatic tumorigenesis. In addition to Kras mutation, the majority of all pancreatic adenocarcinomas express abnormally high levels of the growth factors that bind to EGFR as well as high levels of EGFR itself. Due to this prevalence in human tumors and in early precursor lesions, we hypothesize that EGFR signaling contributes to early stages in pancreatic neoplasia. We will test this hypothesis in two ways, by increasing or by decreasing EGFR signaling in conjunction with activation of the Kras oncogene, using mouse models of pancreatic ductal adenocarcinoma. We will increase EGFR signaling via transgenic overexpression of the growth factor HB-EGF, and we will decrease EGFR signaling by using mice with a mutation in the Egfr gene. These experiments will indicate what stage of tumorigenesis is affected by EGFR signaling as well as determining if and when EGFR is an appropriate chemotherapeutic target in pancreatic cancer patients. This work will also lead to further studies on the mechanisms of EGFR action and regulation in pancreatic tumorigenesis. Relevance: Pancreatic cancer is the 5th leading cause of cancer deaths in this country. This is due both to difficulty in detecting early stage cancers and to this cancer being refractory to traditional therapies. The studies proposed here investigate EGFR signaling as a potential biomarker and/or therapeutic target, by studying its effects on tumorigenesis in a mouse model of pancreatic cancer. [unreadable] [unreadable] [unreadable]